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Search: Genetic[Title] AND Stress-Induced[Title] AND Loss[Title] AND NG2[Title] AND Glia[Title] AND Triggers[Title] AND Emergence[Title] AND Depressive-like[Title] AND Behaviors[Title] AND Reduced[Title] AND Secretion[Title] AND FGF2[Title]

Abstract

NG2-expressing glia (NG2glia) are a uniformly distributed and mitotically active pool of cells in the central nervous system (CNS). In addition to serving as progenitors of myelinating oligodendrocytes, NG2glia might also fulfill physiological roles in CNS homeostasis, although the mechanistic nature of such roles remains unclear. Here, we report that ablation of NG2glia in the prefrontal cortex (PFC) of the adult brain causes deficits in excitatory glutamatergic neurotransmission and astrocytic extracellular glutamate uptake and induces depressive-likebehaviors in mice. We show in parallel that chronic social stress causes NG2glia density to decrease in areas critical to Major Depressive Disorder (MDD) pathophysiology at the time of symptom emergence in stress-susceptible mice. Finally, we demonstrate that loss of NG2 glial secretion of fibroblast growth factor 2 (FGF2) suffices to induce the same behavioral deficits. Our findings outline a pathway and role for NG2glia in CNS homeostasis and mood disorders.

(A) Paradigm used for NG2 glial cell ablation in the iDTR adult mouse brain using systemic Diphtheria Toxin (DT) administration. DT (50 ng/ul) was injected once daily for 7 days; days post DT (dpDT).(B) Representative images and quantification of depletion efficiencies in different brain regions including cortex, hippocampus, subcortical white matter and striatum. Arrows, NG2+ glial cells.(C) NG2 glial cell numbers in different cortical regions of control and iDTR mice at 7DT.(D) NG2glia (PDGFRα+), neuron (NeuN+), astrocyte (glutamine synthase; GS+), and mature oligodendrocyte (CC1+) numbers in the PFC of control and iDTR at 7DT.(E) Representative confocal images of MBP immunostaining from control and iDTR mice at 7DT.(F) Protein extracts from the PFC were used to analyze total expression levels of MBP and MOG at 7DT.(G) The number of mature oligodendrocytes is rapidly replenished during the DT paradigms as assessed by the newly formed mature oligodendrocytes (BrdU+CC1+ cells) at 5 days after 7DT (5dpDT). Error bars, mean ± SEM (*p < 0.05, **p < 0.01; t-test) n = 5–7 per group. Scale bars, 40 μm.See also .